The Anatomy of Mood -- Biology and the Brain

Scientists are beginning to understand the connection between brain atrophy, neurogenesis, and depression. How does this affect our understanding of the role of antidepressant medication? Johns Hopkins doctors explain

What happens within the brain when a person is depressed? Our concept of that is rapidly shifting, thanks to work in brain imaging and molecular medicine.

In the late 1990s, several lines of research began turning our concept of mood disorders upside down. Taken chronologically, the first step was research showing that neurogenesis -- the birth of new brain cells -- can continue throughout life. The second was evidence that depression is associated with loss of volume in parts of the brain.

Most of us remember being told at some point that were born with all the brain cells well ever have. Not true. We now know that the process of neurogenesis is an ongoing one, with new brain cells being born even as old brain cells die off. Researchers have also found that depression appears to inhibit this birth of new brain cells. And that may help explain the second line of research -- why people whove had depression are likelier to have a smaller hippocampus (a part of the brain that plays a role in emotion and is associated with memory and learning). The more severe and long-lasting the depression, the greater the loss of brain volume.

This process of brain atrophy also affects the frontal lobes, which are involved in managing emotional reactions. The good news is that most of the change seems to be related to cell shrinkage, rather than outright cell death, and thus can potentially be reversed. Genetic studies have also found that a subgroup of people are more susceptible to this process of brain atrophy.

Where does this leave familiar neurotransmitters such as serotonin and norepinephrine? They are still understood to play a significant role in mood disorders -- but with a new twist. Most people are familiar with the research that underlies the use of fluoxetine (Prozac) and similar antidepressants. These drugs block the reuptake of certain neurotransmitters at receptor sites in the brain, thus increasing the concentrations of serotonin and other neurotransmitters in the synapses (gaps) between cells -in the brain. This increase is believed to be responsible for the elevation of mood.

The twist? More recently, instead of focusing on tinkering with the level of neurotransmitters between cells, researchers have looked at what happens when the neurotransmitter binds to the cell membrane. The reactions that then go on inside the cell are now thought to be more important to the cells functioning than the binding of the neurotransmitter to the outside. For instance, researchers have found that antidepressants increase levels of brain derived neurotrophic factor (BDNF), which helps nourish neurons, helping them become more active and make more connections to other cells. Researchers also have found that antidepressants are involved in neurogenesis -- at least in rats, increasing the production of new neurons in the rat hippocampus.

In animal studies, stress puts a halt to the process of neurogenesis. Under stress, existing cells shrink and the total number of cells decreases. Exercise and environmental enrichment, on the other hand, have a beneficial effect.

In humans, there are hints that exercise may help reverse brain atrophy. Treatment with antidepressants also has been found to be effective, although the extent of the response varies among individuals and may be moderated by how severe a persons depression has been, and how often it has recurred. And psychotherapy still has a role to play because how we interpret a stressful event can have a significant impact on our emotional response and ability to recover.

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